Vitamin D and Sex
Authors: J. Martin, P. Lopez
Journal: Journal of the American Society of Nephrology (2007)

Whereas in the past vitamin D was exclusively viewed as an indispensable agent in the homeostasis of calcium phosphorous metabolism, recent findings suggest a much broader role and “new assignments for an already busy receptor” (1). The article by Martin and Lopez (2), which illustrates another unexpected role of vitamin D, is somewhat far out for nephrologists but is of interest because it illustrates the incredible diversity of nonclassical actions of vitamin D. In the animal kingdom, the selection of mates is controlled by social signals. In the past, attention had been focused mainly on visual (peacock, stag) and acoustic—sonic or ultrasonic—(birds, mice) signals. What is the biologic “purpose” of such signals, which are wasteful and costly to the male? It was thought that such display, for instance, the handicap of diverting great amounts of calcium into the antler of the stag (interestingly also under the influence of active vitamin D [3,4]) provides information to the female: The male that can afford such waste is presumably sufficiently healthy to gather high-quality food and will sire offspring that are fit for survival; in other words, the cost is correlated with the male signaler’s quality such that such handicap actually serves as a biologic signal (5). The article by Martin and Lopez (2) culminated a series of observations on the Iberian rock lizard (Lacerta monticola). It had been shown that the males of this species (6) secrete a great number—44—lipophilic compounds through the precloacal pores of the femoral gland, mainly cholesterol, but also several carboxylic acids, alcohols, squalene, and a lactone as shown by gas chromatography–mass spectrometry. This had been documented in other lizard species as well (7). Of note was the considerable variability of the composition of the secretion that reflected the health condition of the males. The authors speculated that the composition provided chemical cues to the female as the basis for the female choice of a male. But which of these compounds was providing the signal? One intriguing finding in view of the role of vitamin D in immunoregulation (8) was the observation that provitamin D (cholesta-5,7-dien-3-ol) in the femoral secretions of male lizards was correlated to good T cell–mediated immune responses (9). Such males that secreted high amounts of provitamin D were preferred by females. Provitamin D is known to be transformed in lizards under the influence of ultraviolet light to vitamin D (10). Furthermore, Martin and colleagues (11) found that lizards that had higher amounts of vitamin D products in their femoral gland secretions had not only better T cell–mediated immune responses but also higher body weights, greater numbers of blue spots, and greater numbers as well as asymmetry of the pores of the femoral gland. With the present intervention trial (2), the authors provided definite evidence for the hypothesis that it is provitamin D that acts as a pheromone. (Pheromones are chemicals that are produced by organisms and transmit a message to other members of the same species.) The working hypothesis tested was the postulate that the quality of the diet (i.e., its vitamin D content) affected the chemical characteristics of femoral gland secretions of male Iberian rock lizards. To prove this hypothesis, the authors maintained lizards on an insect diet and administered commercial vitamin D3 or water as control. The readouts were as follows: The composition of femoral gland secretions by gas chromatography–mass spectrometry The tongue-flick test in females as a bioassay to assess the detection of chemical cues by the female in swabs that were impregnated with the femoral gland secretions of males that were supplemented with vitamin D or with water as control The selection by females of paper strips that were impregnated with and thus scent-marked by secretions from males that were supplemented with vitamin D or water. Results of the Readouts A significant increase in provitamin D (cholesta-5,7-dien-3-ol) in femoral gland secretions was found in the male lizards that were supplemented with vitamin D but not in control males. Females responded to all swabs but significantly more to those that were impregnated with the secretions of vitamin D–supplemented males and also to swabs that were impregnated with pure cholesta-5,7-dien-3-ol. Females spent more time on the paper strips that were scent-marked by the femoral gland secretions of vitamin D–supplemented males. The results document that vitamin D supplementation enhances the attractiveness of male lizards to female lizards as a result of higher concentrations of provitamin D in the femoral gland secretions. High provitamin D in the secretions of the femoral gland, similar to the mammalian apocrine glands in groin and axilla, indicates to the female that the male is healthy enough to allow him the luxury of diverting a greater amount of provitamin D by allocating it to the secretions. The ventral location of the glands allows the passive deposition of the secretions on the ground as the male lizards move trough their home territory, thereby scent-marking their territory, for which females then show a preference. The scent signals that the male was able to obtain a better diet, rich in vitamin D, thereby increasing for the female the probability of mating with a male of high quality. Male pheromones of different chemical composition are widely known in other amphibians (12) but also widely demonstrable in vertebrates from goldfish (13) to mammals (14). They are not restricted to males, but reciprocal signaling is documented by female pheromones that affect male sexual behavior in amphibians (15) and mammalians (16,17). Primates have two main olfactory subsystems: (1) The main olfactory epithelium, which binds volatile odorants and mediates the conscious perception of odors, and (2) the vomeronasal organ, which binds pheromones as social signals and is responsible for behavioral and neuroendocrine responses (18,19). The more primitive vomeronasal system and its genes have shrunk in the evolution of primates (20), and only five potential functional vomeronasal receptor genes have been found in humans (21). Nevertheless, it would be premature to exclude generally the action of pheromones in humans (22). To the dismay of human males, the pheromones that attract females have not yet been identified, but some remarkable findings have recently been made. What is known today is that human urine, saliva, and sweat, as in lizards (23), contain soluble and volatile products that serve as specific MHC-linked odor cues (24). MHC-dependent mate preference in humans is suggested by the observation that females scored male odors as more pleasant when the men differed in their MHC than when they were more similar (25–27). On the basis of animal experiments, it has been argued that MHC-based mating preference selectively influences reproductive success and has adaptive advantage by avoiding inbreeding and enhancing immune competence (e.g., against parasites [27,28]). Generally, the impact of odors on human behavior must not be underestimated, as the perfume industry knows. Compared with the past, odors may no longer play as important a role because washing habits and hygiene have become more civilized, but the importance of odors in ancient times still underlies the harshest expression of antipathy in the German language: “Ich kann ihn nicht riechen”—I cannot stand his odor. Or the Spanish expression, “Olor de sanctitad” (odor of sanctity): In Spain after the reconquest, it was a crime to use a bathtub, because this aroused suspicion that the respective individual was a Maranon, a secret Jew, and this led to condemnation by the Holy Inquisition and auto-da-fé. The most observing Christian monks, in contrast, washed only once per year, ironically on Good Friday, and their odor was such as one would expect –whence the expression, “Olor de sanctitad” (odor of sanctity). In humans, the vitamin D status is a priori not likely to signal male health, and it is therefore not terribly likely, although not totally excluded, that provitamin D plays a role as a pheromone in humans as well, but this observation in the amphibians illustrates that this substance still holds surprises and has a plethora of nonclassical actions, for example, in immune function (8), β cell function (29,30), apoptosis (31), cell-cycle control (32), and control of renin secretion (33), to mention only a few. Deservedly, these nonclassical actions, called “pleiotropic” (literally “directed in diverse directions”), have recently attracted considerable interest in the renal community (34).